Acute myelogenous leukemia (AML) is a heterogeneous disease composed of numerous sub-classifications displaying a wide spectrum of phenotypes. (See Berman, E., Curr. Opin. Hematol., 4: 205-11 (1999) and Bruservd, O. et al., Stem Cells, 18: 157-65 (2000).) The major therapeutic approach to this disease has been the use of chemotherapeutic agents with associated life-threatening toxicity. Although non-specific in their effects, these regimens have significantly increased the survival of AML patients. (See Saez, R. A., Cancer Control, 4: 399-406 (1997); Bruservd, O. et al., Stem Cells, 18: 343-351 (2000); and Stein, A. S. et al., Leukemia, 14: 1191-1196 (2000).) Recently, more targeted therapy has been developed. Treatment of acute promyelocytic leukemia (APL) patients with trans-retinoic acid (tRA) results in the differentiation of the cells with 90 percent of the patients achieving a complete remission. (See Chen, Z. X. et al., Blood, 78: 1413-1419 (1991); Castaigne, S. et al., Blood, 76: 1704-1709 (1990); and Warrell, R. P. et al., N. Engl. J. Med., 324: 1385-1393 (1991). tRA exerts its effect by modulating gene expression through its role as a ligand to the retinoic acid nuclear receptors (RARs) with the subsequent binding of this complex to the RARE consensus sequences located in the regulatory regions of retinoid-responsive genes. The selective sensitivity of APL cells to tRA-mediated differentiation resides in their specific expression of a unique PML-RARα fusion product with subsequent maturation arrest of these cells at the promyelocyte stage; exposure of these cells to a micromolar concentration of tRA allows for the degradation of the PML-RARα fusion product and restitution of normal RARα receptor function with subsequent maturation of the APL cells.
Z. M. Shao et al.(1995) have recently shown that the retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalenecarboxylic acid (AHPN) is a potent inducer of apoptosis in a number of cell types. Both natural and synthetic retinoids exert their biological action through their binding to and activation of specific RARs and retinoic acid X nuclear receptors (RXRs). These receptors complexed with ligand and bound to specific regions in the promoters of genes designated as retinoid response elements (RAREs and RXREs) modulate gene expression. AHPN does not bind to the RXRs, is an extremely poor binder and transactivator of the RAR subtype α, but at 1 μM binds and transactivates RARβ and RARγ. Whether AHPN induces apoptosis through activation of these receptors is still controversial. AHPN exposure results in apoptosis of the human leukemia cell line HL-60R, which lacks functional RARs, and the cell line K562, which is resistant to the antiproliferative actions of tRA. These results suggest that AHPN induces cell death at least in myeloid leukemia cells through a novel pathway that does not involve its direct interaction with the retinoid receptors. AHPN also causes the rapid activation of the MAPK kinase pathway by inducing the activation of the p38 and JNK kinases within 1 hour. Activation of these kinases is not observed following exposure of the cells to standard retinoids that function through classical RAR/RXR-signaling pathways. JNK activation has been implicated as a major player in the induction of apoptosis by a number of agents and has recently been shown to result in p53 activation and subsequent p53-mediated-apoptosis in sympathetic neurons.
The ability of AHPN to induce apoptosis in the cell line ALL-REH, which was obtained from a patient with acute lymphocytic leukemia, was examined. AHPN treatment lead to stimulation of caspase 3 activity, which, in turn, resulted in the generation of a unique Bcl-XL cleavage product that promotes apoptosis. AHPN induced apoptosis in ALL cells obtained from patients. Unfortunately, the concentrations of AHPN required to induce leukemia cell apoptosis in a cell culture produced adverse side effects when administered to mice. These results strongly suggest similar toxicity when administered to humans.
Therefore, a continuing need exists for compounds that are more useful inducers, or inhibitors, of apoptosis or apoptosis preceded by cell-cycle arrest. In addition, there is a need for pharmaceutical compositions and methods for treating mammals with leukemia or other forms of cancer or for treating disease conditions caused by apoptosis of cells.